The discovery that the detection limit of potentiometric sensors may be improved by 3 to 6 orders of magnitude of traditionally accepted levels have drastically changed the field of ion sensing. In this continuation proposal, new avenues will be explored to more completely assess the limits of such sensors and to design novel sensing concepts based on ion fluxes at ion-selective membranes. Since potentiometry, as one-dimensional technique, is not subject to scaling laws, the limits of potentiometric sensors will be explored in confined sample volumes. This knowledge will be used to design ultra-sensitive DNA detection devices based on metal nanoparticle probes that would be potentiometrically detected after oxidation. Potentiometry will be coupled to analyte enrichment processes, in analogy to their voltammetric counterparts for a further drastic decrease in detection limit that may surpass that of any other electrochemical method. Ion fluxes at ion-selective membranes, induced chemically and galvanostatically, will be used to design 10-fold more sensitive measuring devices than in traditional potentiometry, which will be very useful for electrolyte and drug monitoring. The perturbance of such fluxes by surface binding events will be used to explore novel approaches to biosensing at liquid-polymer interfaces.